Ovulation induction therapy is safe. critically evaluate this statement.

Ovulation induction is the use of pharmacological agents to stimulate the ovaries to allow antral follicles to mature and rupture to release ova. Ovulation induction is one of the most important and widely used interventions in modern fertility treatment all over the world. Indications include:

Treatment of WHO group 1 and 2 anovulation

To obtain ova for IVF.

The drugs which are used are :

Oral agents Clomiphene citrate

Letrozole

Injectables HCG

Human menopausal gonadotropin

Recombinant FSH

GnRH

Even though these drugs are being widely used, they are not 100% safe. Safety of ovulation induction has been a hot topic in modern gynaecology. The risks may be common to ovulation induction or specific to a certain pharmacological agent.

Risks of ovulation induction therapy include

Ovarian hyperstimulation syndrome
Multiple pregnancies
Ectopic pregnancies
Common side effects of the durgs
The long term risk of developing borderline ovarian tumors.
Terratogenic effects

Ovarian hyperstimulation syndrome is an excessive and unwanted response to ovulation induction which ultimately has a negative effect on the patient. It can be mild, moderate, severe or critical.

Due to abnormal cytokine mediated inflammatory response the vascular permeability is increased and leakage of fluid into the third spaces occurs. There is hypovolaemia, hypoosmolality, hyponatremia, believed to be mediated by VEGF. Even though in mild cases patients will have minimal symptoms, patients will need hospital admission in other instances and in severe and critical conditions will need ICU care with a multidisciplinary team approach. Critical OHSS is associated with multi-organ failure involving liver and renal failure pulmonary edema, respiratory failure, deep vein thrombosis, coagulopathy and death. There is no specific treatment. Usually supportive therapy is given but in refractory cases termination of pregnancy may be required.

Letrozole and clomiphene have the lowest association (5%) with OHSS and gonadotropins have highest risk. The risk is dose-dependent. Patients with high antral follicle count, high AMH values, PCOS and young patients will have a higher risk of OHSS. Use of the lowest possible dose to achieve the desired ovarian response with routine follicle tracking will reduce the risk of OHSS. Antagonist cycle protocol with agonist trigger for ovulation will reduce the risk in high risk patients (PCOS). When there is a risk of OHSS avoiding HCG trigger and embryo replacement in the same cycle will reduce the risk of OHSS in IVF cycles. Early detection and appropriate treatment with MDT approach will reduce the complications.

When it comes to common side effects, 10% of patients on clomiphene citrate will have hot flushes. Apart from common GI side effects, depression, convulsions, hair loss, increased pressure in the anterior Chamber of the eye causing scotoma also have been reported. clomiphene is contraindicated in patients with hepatic disease, ovarian cysts and unknown pregnancy.

Commence treatment with a low dose and avoid a dose higher than 150 mg to minimize all the above complications

Common side effects of letrozole include:

Letrozole is preferred to clomiphene in ovulation induction for PCOS because of the reduced risk of:

OHSS
Multiple pregngnacy
Endometrial atrophy
Impairment of the quality of cervical mucous

Major side effects of letrozole are minimal comparative to clomiphene citrate but there has been divided evidence on its teratogenic potential. Initial studies showed that it is associated with increased cardiac and bone anomalies even though newer evidence has disproved this argument. There have been concerns regarding association between ovulation induction and malignancies and autism in the offspring. However none of them have been scientifically proven.

In level 2 treatment ovulation induction is associated with multiple pregnancy. The risk is ascending in order from letrozole, clomiphene citrate (7- 10 %) to gonadotropins. Mono follicular development should be the target and the minimal drug doses should be used. Multiple pregnancies increase the rate of maternal complications such as hypertension, gestational diabetes, anaemia and fetal complications such as increased rates of miscarriages preterm labour, fetal growth restriction and intrauterine death. It is also associated with significant impact to the health economy.

The Theoretical the risk of ovarian malignancy as a result of ovulation induction has been widely discussed. However, only a few research has been done on this topic. According to that induction therapy is associated with increase of borderline ovarian tumors but not with any other invasive malignancy including ovarian and breast malignancies. NICE has implemented a safety margin of 6 cycles for consecutive ovulation induction.

While ectopic pregnancies occur in 1% to 2% of naturally occurring pregnancies, in gonadotropin cycles the rate is slightly increased. Ectopic pregnancies can be life threatening and require treatment with medication or surgery. In less than 2% of gonadotropin cycles ovarian torsion can occur, which will require additional treatment.

In some women, the injection may cause a local skin irritation. It is extremely rare to have an actual allergy to medication. Some women may experience breast tenderness, headaches, or mood swings due to gonadotropins.

As discussed above all forms of ovulation inductions have their own risks for the patient.

The following can be done to increase the safety of ovulation induction

Use non pharmacological methods first
Weight reduction and metformin in group 2 anovulation
Weight increase, stopping excessive exercise, review of prescribed drugs, avoidance of unprescribed drugs and avoidance of stress in WHO group 1 anovulation
Start treatment with the lowest possible dose of drugs and increase the dose gradually, especially to prevent OHSS and multiple pregnancy.
Give gonadotropins only if there is no response to oral drugs
Perform follicular tracking from the start when using gonadotropins and from the 10^th-12^th day when using oral drugs.
Stop the treatment if there is any suspicion of OHSS and treat effectively.
Cancel the treatment cycle and avoid further treatment such as hCG injections and IUI if there are several pre-ovulatory follicles.
Avoid implanting multiple embryos in IVF cycles.
Restrict the treatment to 6 cycles because of the rare possibility of borderline ovarian tumours.

Judicial use of therapy which is tailored for each patient will reduce the risks and increase the safety of ovulation induction. It is also essential to discuss these concerns with the patient before embarking on a treatment plan. Further research will alleviate grey areas in our knowledge on safety. Competence of early recognition and evidence based management of these complications should be an essential part of fertility treatment service. All this will make the journey towards fertility with ovulation induction much safer.